Increasing evidence links antibodies immuno-reacting with gangliosides GM1 and GD1b with abnormalities in human motor neurons. IgM serum monoclonal, or M-proteins, from patients with motor neuron disease (MND) bind specifically to a determinant shared by these gangliosides. Autoantibodies binding to these gangliosides have been found in MND patients without M-proteins. Therapy directed at reducing autoantibody concentration has led to improvement of the neurologic disorder in several of these patients. GM1 is located on the external surface of motor end plates. GD1b contains the receptor for tetanus toxin which is internalized and carried to the motor neuron perikaryon by retrograde transport. Binding to these gangliosides would therefore provide antibodies with direct access to motor neurons. MND patient M- proteins with anti-GM1/GD1b reactivity have been demonstrated to immunostain human motor end plates. We propose to examine the effects on motor neurons by antibodies directed against these two gangliosides. In addition to utilizing patient M-proteins we will generate mouse monoclonal antibodies against GM1 and GD1b. Studies will involve immunocytochemistry, animal models and tissue culture. This project is designed to identify mechanisms of disease relevant to patients with MND.